I’m no expert on evolutionary theory, but I do think it’s pretty cool, especially when applied to the major histocompatibility complex; so when Razib pointed out a paper on the evolution of MHC I figured I should write a post about that paper.

This is not that post.

First, as I started to review the background — the various possible kinds of evolutionary drives for MHC diversity — things got a bit too complicated for one post, and I decided I’d be better off splitting things up into several background posts. (Especially since, as I say, I’m no expert, and I can take advantage of a more leisurely review.) Second, as I poked around the literature, I ran across a particularly neat paper1 that I couldn’t resist talking about.

The major histocompatibility complex region is the most polymorphic region in the genome, for most (if not all) vertebrates; MHC class I and II genes evolve with dramatic speed (“During the timeframe of mammalian evolution, the lifetimes of a functional class I locus are short and those of individual alleles even shorter.”2 ) (To the right is an illustration of that, a phylogenetic tree showing relationship of the known alleles for a single MHC class I locus, HLA-A — not even the most diverse locus [the IMGT/HLA Database lists 580 HLA-A alleles, compared with 921 HLA-B] . This was made from the dbMHC‘s data. Click on the figure for a larger view.)

The question is: Why is it so diverse? As I understand it — and if any readers know more than me, which wouldn’t be all that hard, feel free to jump in and correct me — the general term for this situation (in which there is a drive to maintain multiple alleles in a population) is balancing selection, and the most common explanations for the phenomenon in MHC are heterozygote advantage (which is not quite the same as overdominance), frequency-dependent selection, disease-specific selection, sexual selection, maternal-fetal interactions, and drift. (As I understand it, none of those possibilities are mutually exclusive.) The paper Razib talked about was looking at heterozygote advantage, and concluded that overdominant selection was not a factor — though, as I observed in the comments there, the literature is really back and forth on that, and there are some instances where overdominance may be important. I will try to give an overview of that some other time.

This brings me to the San Nicolas Island fox (Urocyon littoralis dickeyi). Foxes colonized six of the Channel Islands off California between 16000 and 800 years ago (see the map to the left, click for larger version). These small, isolated populations are extraordinarily homogenous; in particular, the San Nicolas Island foxes, with an estimated population of 247, had no variation whatsover in any of the alloenzymes, minisatellites, or microsatellites examined (“for which the probability of genetic identity is commonly <1 in several million“). This was because of a recent genetic bottleneck, as well as earlier ones:

Initial simulations clearly suggested a severe bottleneck (to an effective size of 10 individuals or fewer for one or two generations, followed by 12 generations of population growth) was necessary to explain near monomorphism at the 18 loci. … This extreme scenario is consistent with the recent population crash of island foxes on the east end of Santa Catalina Island where the population was reduced from >1,000 to 10 individuals in a single generation due to a canine distemper epidemic in 1999. A similar event may have occurred on San Nicolas Island …

Of course, there’s an exception to the homogeneity, and of course it turns out to be the MHC. Within the MHC region these foxes are diverse: “These values of heterozygosity are similar to those in larger populations of island foxes and suggest the action of intense balancing selection over a sizable genomic interval within the fox MHC class II.“

So in spite of a drastic bottleneck that virtually eliminated genetic diversity, balancing selection has maintained, or generated, diversity within this specific locus (and perhaps only this locus; but the authors point out that the same effect may be true on other fitness-related genes, though probably not to the same extent).

This does not, I think, speak to one particular mechanism for the balancing selection, but it does tell us just how much selective pressure gets applied.

Given our demographic scenario for San Nicolas Island foxes, we found that periodic selection coefficients for the microsatellite loci as high as 0.5-0.95 are required to maintain heterozygosity values near 0.62 at microsatellite locus FH2202 and 0.36 at the DRB locus. These selection coefficients are much larger than those reported in natural (range: 0.05-0.15) and human populations (range: 0.19-0.39) for a locus under balancing selection.

Is it possible there is some unusual mechanism for mutation in or change of MHC class I and II genes? Might they be self-mutilating or something? Might they interact with something outside the DNA itself? Are they in a particularly vulnerable position physically on the DNA? Do they “tell” the RNA during transcription, “hey, wing it for the next few bars”?

The idea that the MHC region is particularly prone to mutation is a good one — it’s been one of the candidate explanations. However, it’s not likely that that’s the whole story, and it’s probably not a significant part. Without digging into the details, there are two issues to deal with: The generation of new MHC alleles, and the selection that causes the new alleles to spread throughout the population. Self-mutilation would increase the number of new alleles, but wouldn’t help them spread. (What you’d probably see would be a very large number of new alleles, each within a very tiny localized population.) In fact, analysis of the new alleles that form (as in the foxes here) suggests that they’re being very strongly selected for. In general, the bone of contention is the nature of the selection on the new alleles once they’re formed.

[…] times more variable (more alleles) than the average genomic chunk. Even populations that are otherwise inbred and lack diversity throughout their genome, rapidly evolve, or maintain, MHC diversity. There is […]

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